The candidate is an MD/PhD trained clinical neurologist with the career goal to investigate the mechanisms of neurodegeneration in peripheral neuropathies, using axonal Charcot-Marie-Tooth (CMT) as a prototypical disease. The career development plan will be jointly mentored by Dr. Alan Pestronk, a clinical expert in neuromuscular disorders, and Dr. Jeffrey Milbrandt whose lab focuses on molecular mechanisms of axonal degeneration and peripheral neuropathy - a unique merger allowing the candidate to become a successful independent investigator in this field. CMT neuropathies are among the most common inherited conditions of the nervous system, and currently are without treatment. They provide an opportunity for the clinician-scientist to understand the mechanisms of axonal degeneration in the peripheral nervous system, which likely will have broader implications for neurodegenerative disorders. Mitofusin 2 (MFN2) mutations are the most frequently identified cause of the axonal form of CMT (CMT2A), but the mechanism by which they lead to axonal degeneration is unknown. MFN2 is a mitochondrial membrane protein that is a critical component of the mitochondrial fusion apparatus, required for proper mitochondrial function. Our primary hypothesis is that MFN2 mutations lead to altered axonal mitochondrial transport and/or mitochondrial fusion, resulting in mitochondrial dysfunction, energy depletion and degeneration of distal peripheral axons. We will test this hypothesis by 1) introducing disease mutant forms of MFN2 seen in CMT2A patients into cultured sensory neurons, and examining their effect on axonal mitochondrial transport, mitochondrial fusion and oxidative function; and 2) generating a transgenic mouse model of CMT2A to study the detailed pathogenesis of the disease, corroborate our in vitro findings in an in vivo disease model, and to potentially provide a means of testing therapeutic agents for peripheral neuropathy and axonal degeneration in future studies. Relevance: Peripheral neuropathies, particularly those caused by metabolic disorders such as diabetes are a major cause of morbidity in the United States, yet the mechanisms of peripheral neuropathy remain poorly understood and there are no effective treatments. This proposal outlines research to understand the mechanism of an inherited form of peripheral neuropathy, in the hopes that this will provide insight, and eventually lead to effective treatments, for more commonly encountered types of neuropathy. [unreadable] [unreadable] [unreadable]